Our group has previously shown a markedly different time course in the developmental measures of serotonin synthesis in children with autism as compared to non-autistic children using PET imaging (Funded by NICHD RO1 HD34942). These data are consistent with the notion that serotonin synthesis is abnormal during critical periods of brain development in autistic children. Specific to this project, we showed that serotonin synthesis capacity in children less than the age of 6 years showed significantly lower values than non-autistic children. Since serotonin is known to be an important factor involved in postnatal synaptogenesis, we hypothesized that one approach to the treatment of core features of autism pharmacologically is the use of serotonin agonists in children less than the age of 6 years. The goal of this treatment is to provide a more normal modulation of synaptic plasticity in autistic children during the early childhood years. For this study, we chose the 5HT1A serotonin agonist buspirone. The rationale for the choice of buspirone was based upon basic studies demonstrating a prominent role of the 5HT1A receptor in the regulation of postnatal synaptogenesis. Our long-range goal is to utilize neuroimaging markers in autism, which can be used in the rational design of treatment in groups or subgroups of children with autism. The goal of this study is to test further the safety and efficacy of buspirone in a large group of young children. This trial is guided by pilot study results funded by NICHD through the Pediatric Pharmacology Research Unit (PPRU) network. In our pilot study, we demonstrated improvement in social interaction, repetitive behavior, sensory dysfunction and anxiety with 3 months of buspirone treatment. A subset of the children continued in a 6-month open label study and showed further improvement by the end of the open label study. In addition, serotonin synthesis capacity measured with alpha[11C]methyl-L-tryptophan (AMT) positron emission tomography (PET) was related to the response to buspirone in the pilot study, while plasma serotonin was not. Thus AMT PET will be tested as a biomarker for drug response.